Project Summary Ultraviolet radiation (UVR) from sunlight has been epidemiologically identified as a leading risk factor for melanoma development. However, the mechanistic details of how sunlight UVR causes melanoma are still being elucidated. Recent studies revealed tremendous amounts of UV-induced genetic mutations in melanoma genomes compared to most other types of tumors. Furthermore, UV-induced mutagenesis accelerates melanoma progression and recurrence. These studies highlighted the need to better understand the molecular mechanisms protecting against environmentally UVR-induced mutagenesis, and to delineate why they fail to work in melanoma, providing answers that could pave the way for personalized prevention and treatment of this often-fatal illness. This project will meet this challenge, capitalizing on our recent discovery of an autophagy modulator as a bona fide UV protector through distinct mechanisms and its strong correlation with reduced melanoma risk. Our primary hypothesis is that reduced capacity of UV- induced photolesion repair and adaptive skin pigmentation represents the main reasons of genetic instability of melanoma cells and is responsible for melanoma predisposition. To test the hypothesis, we will first dissect the mechanism by which UV-induced photolesion is repaired in melanocytes to provide UV resistance (Aim 1), identify the mechanism governing UV-induced melanogenesis and pigmentation to prevent UV penetration (Aim 2), and determine how and to what extent these mechanisms of action impact UV sensitivity and neoplastic expansion of melanoma using inducible transgenic and humanized murine models (Aim 3). These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, live-cell imaging, and physiological assays in cells and in mice with targeted mutations in UV resistance genes. Together, we anticipate that our studies will identify new UV- protecting mechanisms that regulate melanoma disease penetrance and provide compelling in vivo validation of a novel prognostic and predictive biomarker in melanoma.